1-(3,4-Dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine

ABSTRACT

1-(3,4-DIMETHOXY-PHENYL)-4-METHYL-5-ETHYL-7,8-DIMETHOXY-5H-2,3-.Iadd.benzo.Iaddend.diazepine having the following formula ##STR1## This new compound is non-toxic and pharmacologically active. Its acid addition salts also have useful pharmacological

This application is a continuation-in-part of copending.]. .Iadd.Thepresent application is a reissue application for U.S. Pat. No. 3,736,315issued from a continuation-in-part of copending .Iaddend. applicationSer. No. 688,674 filed on Dec. 7, 1967, now abandoned.

This invention relates to a new benzodiazepine derivative ofpharmacological value. More particularly, it is concerned with the new1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3.[.-diazepine.]..Iadd.-benzodiazepine.Iaddend.having the following formula ##STR2## and its non-toxic salts.

The new compound according to the invention can be conveniently preparedby several methods. According to a preferable method

(a) 3,4,3',4'-tetramethoxy-6-(α-aceto-propyl)benzophenone is reactedwith hydrazine or hydrazine hydrate, the obtained product is transformedwith an acid, preferably with an inorganic acid, to a salt, wherein, ifdesired, the 2 reactions can be simultaneously carried out and thebenzodiazepine is released from the thus-obtained salt by treating withan acid-binding agent, or

(b) an1-(3,4-dimethoxy-phenyl)-3-methyl-4-ethyl-6,7-dimethoxy-isobenzopyriliumsalt is reacted with hydrazine or hydrazine hydrate and, if thehydrazine was not employed in a considerable excess, the benzodiazepineis released with an acid binding agent, and finally, if desired, thefree benzodiazepine is transformed to an acid addition salt by reactingwith an acid.

In the reaction according to paragraph (a) at first3,4,3',4'-tetramethoxy-6-(1-ethyl-2-hydrazone-propyl)-benzophenone isformed. This intermediate compound is new and it is transformed tobenzodiazepine derivative by reacting with an acid. The two reactionscan be preferably carried out simultaneously. Ammonium hydroxide, alkalihydroxides, carbonates and hydrogen carbonates can be convenientlyemployed as acid binding agents.

It is preferable to carry out the above-described reactions in asolvent, such as a lower alphatic alcohol or a mixture thereof. Thereleasing of the salt is preferably carried out in an aqueous medium.

It is mentioned that the free benzodiazepine separates with one mole ofcrystal water, and this monohydrate melts at 95°-115° C. but it losesits crystal water by heating, preferably under vacuum, or byrecrystallizing from an alkanol. The free benzodiazepine having nocrystal water melts at 156°-157° C.

The new compound according to the invention as well as its acid additionsalts can be presented as pharmaceutically acceptable compositions byformulating them alone or with other pharmaceutically active compounds,if desired, together with carrier, binding, filling, surface-active,flavouring, etc. agents usable in the pharmaceutical industry, in any ofthe usual ways, to medicines.

The methods for preparing the starting compounds are described in thetechnical literature as follows:

(a) 3,4,3',4' -tetramethoxy-6 -(α -aceto-propyl)-benzophenone: Ber.75,891 (1942); J.A.C.S. 72, 1118 (1950).

(b) Isobenzopyrilium salts: Ber. 77, pages 6 and 12 (1944); J. Org.Chem. 19, 472 (1954).

The new compound according to the invention and its acid addition saltspossess valuable pharmacological properties. They show an excellenttranquillizing effect. The ED₅₀ per os value of the free base amounts to45 mg./kg. while that of the Meprobamate amounts to about 200 mg./kg.and that of the Trimethoxine to about 130 mg./kg. The effect of the3,4,3',4'-tetramethoxy-6-(1-ethyl-2-hydrazono-propyl)-benzophenoneprepared as intermediate product attains the effect of the minortranquillizing compounds: its ED₅₀ amounts of 160 mg./kg. and its LD₅₀value amounts to 1600 mg./kg.

The new compound according to the invention and its methods ofpreparation are further illustrated by the aid of the followingexamples.

EXAMPLE 1

4.00 g. (0.01 mole) of 3,4,3',4' -tetramethoxy-6 -(1-ethyl- 2-hydrazono-propyl)-benzophenone is dissolved in 20 ml. of methanolsaturated with gaseous hydrogen chloride and the thus-obtainedorange-coloured solution is evaporated nearly to dryness. 20 ml. of a 5%NaOH solution are added whereupon the white 1-(3,4-dimethoxy-phenyl)-4-methyl- 5-ethyl-7,8 -dimethoxy- 5H-2,3-benzodiazepine is separated.The product is filtered and washed with 2×2 ml. of water. The dry rawproduct is dissolved in 10 volumes of isopropanol, clarified withcharcoal and then crystallized. Yield: 2.7 g. (71%). M.P.: 156°- 157° C.

Analysis data for C₂₂ H₂₆ N₂ O₄ (382.45): Calculated (percent): C,69.09; H, 6.85; N, 7.33. Found (percent): C, 69.07; H, 6.63; N. 7.39.

The hydrochloride (C₂₂ H₂₇ ClN₂ O₄) of the 5H-2,3-benzodiazepinederivative decomposes at 217.5° C. and its picrate (C₂₂ H₂₆ N₂ O₄ .C₆ H₃N₃ O₇) at 204° C.

The starting compounds are prepared in the following way:

(a) 3,4,3',4'-tetramethoxy- 6-(1-ethyl- 2-hydrazono-propyl-benzophenone.

A mixture of 38.64 g. (0.1 mole) of3,4,3',4'-tetramethoxy-6-(α-aceto-propyl)-benzophenone, 15 g. (0.3 mole)of 100% hydrazine hydrate and 200 ml. of abs. ethanol is refluxed for 3hours. Thereafter the reaction mixture is held in a refrigerator for anight. The white granular precipitate is filtered, washed with 2× 20 ml.abs. ethanol and dried at room temperature.

Yield: 24.8 g. (62%). Melting point: 134°- 136° C. N, percent: 6.90.

The thus-obtained crude product is crystallized from 8 volumes ofethanol. The obtained product weighs 22.5 g. Melting point: 136° C.

Analysis data for C₂₂ H₂₇ ClN₂ O₄ (418.92). Calculated (percent): C,65.98; H, 7.05; N 7.00. Found (percent): C, 66.16; H, 7.53; N, 7.05.

If one proceeds as described above but only with 0.1 mole of hydrazinehydrate then the product is obtained with a yield of 49% and melts at133°- 136° C.

EXAMPLE 2

A mixture of 3.86 g. (0.01 mole) of3,4,3',4'-tetramethoxy-6-(α-aceto-propyl)-benzophenone, 0.011 mole ofhydrazine or of 60- 100% hydrazine hydrate, 60 ml. of ethanol and 0.005mole of sulfuric acid is boiled for 10 hours. The reaction mixture isevaporated and the residue is treated by the method as described inExample 1.

In this way 2.55 g. of the benzodiazepine derivative is obtained with amelting point of 156° C.

EXAMPLE 3

4.41 g. (0.01 mole) of 1-(3,4-dimethoxy-phenyl)-3-methyl-4 -ethyl-6,7-dimethoxy-isobenzopyrilium-chloride hydrochloride (C₂₂ H₂₆ Cl₂ O₅)are dissolved in 35 ml. of methanol at a temperature of 40° C. Aftercooling to 20°- 25° C., 0.75 g. (0.015 mole) of 100% hydrazine hydratedissolved in 5 ml. of methanol are added whereupon the orange-colouredsolution is getting light yellow. The reaction mixture is evaporated todryness. The residue is digested with 3 ml. of water, cooled to 0° C.and filtered. The obtained yellow hydrochloride of the benzodiazepinederivative decomposes at 205° C. Weight: 3.3 g. After digesting withethyl-acetate, the product decomposes at 217.5° C.

Analysis data for C₂₂ H₂₇ ClN₂ O₄ (418.92). Calculated (percent): N,6.69; Cl, 8.46. Found (percent): N, 6.52; Cl, 8.21.

2 g. of the thus-prepared hydrochloride are dissolved in 15 ml. of waterand the pH of the solution is set to a value of 11- 12 with aconcentrated solution of ammonia or NaOH. A voluminous white precipitateseparates out.

The precipitate is filtered, washed with water and dried at 30° C. untilconstant weight. In this way 1.6 g. product are obtained.

Analysis data for C₂₂ H₂₆ N₂ O₄ .H₂ O (400.46): Calculated (percent): C,65.98; H, 7.05; N, 7.00. Found (percent): C, 65.59; H, 7.29; N, 6.95.

The product loses its crystal water even during recrystallization. 0.5g. of the product are dissolved in 5 ml. of hot isopropanol, thesolution is evaporated to half of its volume and then is put into arefrigerator. The light cream-coloured, transparent granular crystalsmelt at 156°- 157° C. Yield: 0.45 g.

The same end product is obtained if the same method is employed as abovebut 1-(3,4-dimethoxy-phenyl)- 3-methyl- 4-ethyl-6,7-dimethoxy-isobenzopyrilium hydrogen-sulphate (C₂₂ H₂₆ O₉ S) isemployed as starting compound.

EXAMPLE 4

0.01 mole of one of the isobenzopyrilium salts as employed according toExample 3 is dissolved in 50 ml. of lukewarm methanol. 1.25 g. (0.025mole) of 100% hydrazine hydrate are added to the dark yellow solutionwhereupon the solution lightens in colour. The reaction mixture isevaporated nearly to dryness. After adding 20 ml. of water, thebenzodiazepine containing crystal water is filtered and washed with 2× 2ml. of water. The dry crude product (3.3 g.) is dissolved in 10 volumesof isopropanol. The solution is clarified with charcoal. Aftercrystallization 2.8 g. (73.5%) product are obtained with a melting pointof 156°- 157° C.

What we claim is:
 1. The pharmacologically active1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepinehaving the following formula ##STR3## and its nontoxic acid additionsalts.